Long-Lasting Behavioral Interaction Between Perinatal PBDE Exposure and Mecp2308/+ Mutation

Background: Rett syndrome is an autism-spectrum neurodevelopmental disorder caused by mutations in the X-linked gene MECP2 that encodes methyl CpG binding protein 2. MeCP2 is a known epigenetic modulator of gene expression required for postnatal neuronal maturation. A mouse model with a truncation of Mecp2 (Mecp2³⁰⁸) has described social behavioral defects, but does not show the severe neurological phenotype of the Mecp2 null RTT mouse model, and thus is a useful mouse model for genetic and epigenetic risk for autism-spectrum neurodevelopmental disorders. The widespread use of persistant organic polybrominated diphenyl ethers (PBDEs) as commercial flame retardants over the past decade has raised concern about human exposure to this new pollutant and potential effects on the developing brain, particularly in genetically susceptible individuals.

Objectives: To test potential genetic, epigenetic, and environmental interactions by perinatal chronic low-dose exposure to the organic pollutant BDE-47 in an animal model with genetic risk for social and cognitive deficits.

Methods: Mecp2^308/+ dams bred to wild-type C57Bl6J males were exposed daily to BDE-47 (0, 0.03, or 0.1 mg/kg/day orally) for 10 weeks (4 weeks pre-mating, 3 weeks in utero, 3 weeks lactation). Female and male pups (Mecp2^308/+, Mecp2^+/+, Mecp2^308/y, Mecp2^+/y) from the control and low dose treatment groups underwent behavioral testing for sensory/motor neurodevelopment, social behavior (ultrasonic vocalization, social novelty, social barrier interaction), motor behavior (motor challenge, activity chamber), anxiety (elevated plus maze), sensory processing (prepulse inhibition), and learning (Morris water maze). Behavioral endpoints were analyzed with ANOVA separately by sex using genotype and BDE-47 treatment as independent variables and including the interaction. Following behavioral tests, mice were sacrificed and brain and other tissues remove for epigenetic analyses.

Results: The 0.1 mg/kg/day BDE-47 exposure negatively impacted fertility and litter survival specifically in Mecp2-mutant but not wild-type C57Bl6J mice, suggesting an increased genetic susceptibility of Mecp2-mutant mice to BDE-47 in reproductive success. Independent BDE-47 effects were limited to early pre-weaning developmental tests with significant effects on sensory neurodevelopment and ultrasonic vocalizations. In contrast, Mecp2 genotype effects were predominant in juvenile and adult tests showing significant defects in social behaviors and activity. Significant BDE-47/Mecp2 interaction effects were ameliorating for ultrasonic vocalizations and social interaction time, but compounding for adult spatial learning, specifically in the heterozygous females.

Conclusions: The combination of a genetic risk factor and perinatal exposure of a common organic pollutant showed a long-lived compounding effect on spatial learning behavior of female offspring. Because of the specificity of interaction effects in females, X chromosome inactivation and other epigenetic mechanisms involving MeCP2 are further being investigated.